This invention relates to the synthesis of polypeptide chains containing non-peptide bonds and to the chemical modifications of polypeptide chains.
Normally amino acids within a polypeptide chain are bonded together by a covalent peptide bond of the formula --CO--NH--. A variety of enzymes (proteases) can act on this bond and hydrolyze it to break the polypeptide chain into two or more fragments.
Szelke et al. (1982, Nature 299:555) describe the formation of analogs of angiotensinogen by the chemical modification of peptide bonds within the polypeptide angiotensinogen. The modified bonds have the formula --CH.sub.2 --NH--, and some of the analogs containing those bonds were found to have increased potency compared to native angiotensinogen. It was hypothesized that this increased potency was due to the inability of proteases to cleave the non-peptide bond. Some of the analogs were synthesized from dipeptides formed in solution by reduction alkylation of an amino acid with an amino aldehyde, using NaCNBH.sub.3. The dipeptide was purified by gel filtration and ion-exchange chromatography before completion of the synthesis of the analog.